1. Technical Field of the Invention
The present invention relates to novel phenylurea compound inhibitors of the enzyme SOAT-1 (from “Sterol-O-Acyl Transferase-1”, also named ACAT-1 from “Acylcoenzyme A Cholesterol Acyl Transferase”). It also relates to their formulation into pharmaceutical compositions useful in human or veterinary medicine or else into cosmetic compositions and also their non-therapeutic applications.
2. Description of Background and/or Related and/or Prior Art
Compounds having an SOAT-1 inhibitory type of activity are widely described in the literature as having effects in the regulation of biological processes involving cholesterol and derivatives thereof. These properties confer on this class of compounds a marked potential in the treatment or prevention of many diseases and more particularly in dermatology and in cardiovascular diseases or disorders of the central nervous system. Most of the biological effects of the SOAT-1 inhibitors are mediated by the prevention of the synthesis of esters of cholesterol by the enzyme SOAT-1. Among the documents of the prior art describing molecules inhibiting SOAT-1, exemplary are WO 96/10559, EP-0370740, EP-0424194, U.S. Pat. No. 4,623,663, EP-0557171, U.S. Pat. No. 5,003,106, EP-0293880, EP-0433662 and U.S. Pat. No. 5,106,873, which describe compounds for treating arteriosclerosis or hypercholesterolaemia. The therapeutic potential of the SOAT-1 inhibitors in the treatment of cardiovascular diseases and in particular of hypercholesterolaemia and arteriosclerosis is also described in Kharbanda R. K. et al., in Circulation. 2005, 11, 804. The potential of the SOAT-1 inhibitors for the treatment of Alzheimer's disease has also been reported in the literature, for example by Puglielli, L. et al., in Nature Neurosciences 2003, 6 (4), 345.
For their part, U.S. Pat. Nos. 6,133,326, 6,271,268 and WO 2005/034931 describe compounds inhibiting SOAT-1 for inhibiting the production of sebum. In the field of dermatology in particular, it is particularly advantageous to prevent the excessive production of sebum and all the associated conditions.
Sebum is produced by the sebaceous gland. The greatest concentration of sebaceous glands is located on the face, the shoulders, the back and the scalp. The sebum is secreted at the surface of the skin, where it has a major physiological role, associated with the maintenance of the skin barrier and of a micro-environment enabling the regulation of the cutaneous bacterial and fungal flora.
Hyperproduction of sebum is most commonly associated with a skin or scalp of greasy appearance, which is the cause of discomfort and a poor appearance. Moreover, the hyperproduction of sebum can cause seborrhoeic dermatitis and is associated with increased incidence or severity of acne. The esters of cholesterol produced in the sebaceous gland by SOAT-1 are one of the components of the sebum, among several classes of lipids including the triglycerides, esters of waxes and the squalenes, as described by Nikkari, T., in J Invest Derm 1974, 62, 257. The inhibition of this enzyme or of other acyltransferases can thus make it possible to inhibit the production of sebum. U.S. Pat. No. 6,133,326, in particular, describes the inhibition of sebum by inhibitors of ACAT-1 (also called SOAT-1). Nonetheless, at present no treatment utilizing such inhibitors is available on the market. The only treatments to remedy or alleviate disorders linked with hyperseborrhoea are systemic hormonal treatments or systemic treatment with 13-cis retinoic acid, treatments whose side effects considerably restrict their field of application. There is thus a clear medical and cosmetic need for the treatment of disorders and pathologies linked to the hyperproduction of sebum.